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Inactivation of mTORC2 in macrophages is a signature of colorectal cancer that promotes tumorigenesis.
Katholnig K, Schütz B, Fritsch SD, Schörghofer D, Linke M, Sukhbaatar N, Matschinger JM, Unterleuthner D, Hirtl M, Lang M, Herac M, Spittler A, Bergthaler A, Schabbauer G, Bergmann M, Dolznig H, Hengstschläger M, Magnuson MA, Mikula M, Weichhart T
(2019) JCI Insight 4:
MeSH Terms: Animals, Carcinogenesis, Cell Line, Tumor, Cell Proliferation, Cells, Cultured, Colitis, Ulcerative, Colon, Colorectal Neoplasms, Dextran Sulfate, Disease Models, Animal, Female, Humans, Intestinal Mucosa, Kaplan-Meier Estimate, Macrophages, Male, Mechanistic Target of Rapamycin Complex 2, Mice, Mice, Transgenic, Morpholines, Osteopontin, Primary Cell Culture, Prognosis, Survival Rate
Show Abstract · Added November 6, 2019
The mechanistic target of rapamycin complex 2 (mTORC2) is a potentially novel and promising anticancer target due to its critical roles in proliferation, apoptosis, and metabolic reprogramming of cancer cells. However, the activity and function of mTORC2 in distinct cells within malignant tissue in vivo is insufficiently explored. Surprisingly, in primary human and mouse colorectal cancer (CRC) samples, mTORC2 signaling could not be detected in tumor cells. In contrast, only macrophages in tumor-adjacent areas showed mTORC2 activity, which was downregulated in stromal macrophages residing within human and mouse tumor tissues. Functionally, inhibition of mTORC2 by specific deletion of Rictor in macrophages stimulated tumorigenesis in a colitis-associated CRC mouse model. This phenotype was driven by a proinflammatory reprogramming of mTORC2-deficient macrophages that promoted colitis via the cytokine SPP1/osteopontin to stimulate tumor growth. In human CRC patients, high SPP1 levels and low mTORC2 activity in tumor-associated macrophages correlated with a worsened clinical prognosis. Treatment of mice with a second-generation mTOR inhibitor that inhibits mTORC2 and mTORC1 exacerbated experimental colorectal tumorigenesis in vivo. In conclusion, mTORC2 activity is confined to macrophages in CRC and limits tumorigenesis. These results suggest activation but not inhibition of mTORC2 as a therapeutic strategy for colitis-associated CRC.
1 Communities
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24 MeSH Terms
Increased Epithelial Oxygenation Links Colitis to an Expansion of Tumorigenic Bacteria.
Cevallos SA, Lee JY, Tiffany CR, Byndloss AJ, Johnston L, Byndloss MX, Bäumler AJ
(2019) mBio 10:
MeSH Terms: Aerobiosis, Animals, Carcinogenesis, Colitis, Colorectal Neoplasms, Dextran Sulfate, Escherichia coli, Escherichia coli Infections, Female, Gastrointestinal Microbiome, Mice, Mice, Inbred C57BL, Oxygen, Peptides, Polyketides
Show Abstract · Added March 30, 2020
Intestinal inflammation is a risk factor for colorectal cancer formation, but the underlying mechanisms remain unknown. Here, we investigated whether colitis alters the colonic microbiota to enhance its cancer-inducing activity. Colitis increased epithelial oxygenation in the colon of mice and drove an expansion of within the gut-associated microbial community through aerobic respiration. An aerobic expansion of colibactin-producing was required for the cancer-inducing activity of this pathobiont in a mouse model of colitis-associated colorectal cancer formation. We conclude that increased epithelial oxygenation in the colon is associated with an expansion of a prooncogenic driver species, thereby increasing the cancer-inducing activity of the microbiota. One of the environmental factors important for colorectal cancer formation is the gut microbiota, but the habitat filters that control its cancer-inducing activity remain unknown. Here, we show that chemically induced colitis elevates epithelial oxygenation in the colon, thereby driving an expansion of colibactin-producing , a prooncogenic driver species. These data suggest that elevated epithelial oxygenation is a potential risk factor for colorectal cancer formation because the consequent changes in the gut habitat escalate the cancer-inducing activity of the microbiota.
Copyright © 2019 Cevallos et al.
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15 MeSH Terms
Targeted mobilization of Lrig1 gastric epithelial stem cell populations by a carcinogenic type IV secretion system.
Wroblewski LE, Choi E, Petersen C, Delgado AG, Piazuelo MB, Romero-Gallo J, Lantz TL, Zavros Y, Coffey RJ, Goldenring JR, Zemper AE, Peek RM
(2019) Proc Natl Acad Sci U S A 116: 19652-19658
MeSH Terms: Adenocarcinoma, Animals, Carcinogenesis, Disease Models, Animal, Epithelial Cells, Female, Gastric Mucosa, Gastritis, Helicobacter Infections, Helicobacter pylori, Humans, Male, Membrane Glycoproteins, Mice, Mice, Knockout, Nerve Tissue Proteins, Precancerous Conditions, Primary Cell Culture, Risk Factors, Stem Cells, Stomach, Stomach Neoplasms, Type IV Secretion Systems
Show Abstract · Added September 27, 2019
-induced gastritis is the strongest risk factor for gastric adenocarcinoma, a malignancy preceded by a series of well-defined histological stages, including metaplasia. One microbial constituent that augments cancer risk is the type 4 secretion system (T4SS), which translocates the oncoprotein CagA into host cells. Aberrant stem cell activation is linked to carcinogenesis, and Lrig1 (leucine-rich repeats and Ig-like domains 1) marks a distinct population of progenitor cells. We investigated whether microbial effectors with carcinogenic potential influence Lrig1 progenitor cells ex vivo and via lineage expansion within -infected gastric mucosa. Lineage tracing was induced in (Lrig1/YFP) mice that were uninfected or subsequently infected with or an isogenic mutant (nonfunctional T4SS). In contrast to infection with wild-type (WT) for 2 wk, infection for 8 wk resulted in significantly increased inflammation and proliferation in the corpus and antrum compared with uninfected or mice infected with the mutant. WT -infected mice harbored significantly higher numbers of Lrig1/YFP epithelial cells that coexpressed UEA1 (surface cell marker). The number of cells coexpressing intrinsic factor (chief cell marker), YFP (lineage marker), and GSII lectin (spasmolytic polypeptide-expressing metaplasia marker) were increased only by WT In human samples, Lrig1 expression was significantly increased in lesions with premalignant potential compared with normal mucosa or nonatrophic gastritis. In conclusion, chronic infection stimulates Lrig1-expressing progenitor cells in a -dependent manner, and these reprogrammed cells give rise to a full spectrum of differentiated cells.
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23 MeSH Terms
Prevention and Reversion of Pancreatic Tumorigenesis through a Differentiation-Based Mechanism.
Krah NM, Narayanan SM, Yugawa DE, Straley JA, Wright CVE, MacDonald RJ, Murtaugh LC
(2019) Dev Cell 50: 744-754.e4
MeSH Terms: Acinar Cells, Animals, Carcinogenesis, Cell Differentiation, Cell Line, Tumor, Cell Proliferation, Clone Cells, Disease Models, Animal, Gene Expression Regulation, Neoplastic, Humans, Inflammation, Mice, Pancreatic Neoplasms, Pancreatitis, Phenotype, Proto-Oncogene Proteins p21(ras), Signal Transduction, Transcription Factors
Show Abstract · Added September 3, 2019
Activating mutations in Kras are nearly ubiquitous in human pancreatic cancer and initiate precancerous pancreatic intraepithelial neoplasia (PanINs) when induced in mouse acinar cells. PanINs normally take months to form but are accelerated by deletion of acinar cell differentiation factors such as Ptf1a, suggesting that loss of cell identity is rate limiting for pancreatic tumor initiation. Using a genetic mouse model that allows for independent control of oncogenic Kras and Ptf1a expression, we demonstrate that sustained Ptf1a is sufficient to prevent Kras-driven tumorigenesis, even in the presence of tumor-promoting inflammation. Furthermore, reintroducing Ptf1a into established PanINs reverts them to quiescent acinar cells in vivo. Similarly, Ptf1a re-expression in human pancreatic cancer cells inhibits their growth and colony-forming ability. Our results suggest that reactivation of an endogenous differentiation program can prevent and reverse oncogene-driven transformation in cells harboring tumor-driving mutations, introducing a potential paradigm for solid tumor prevention and treatment.
Copyright © 2019 Elsevier Inc. All rights reserved.
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18 MeSH Terms
Differential Cell Susceptibilities to Kras in the Setting of Obstructive Chronic Pancreatitis.
Shi C, Pan FC, Kim JN, Washington MK, Padmanabhan C, Meyer CT, Kopp JL, Sander M, Gannon M, Beauchamp RD, Wright CV, Means AL
(2019) Cell Mol Gastroenterol Hepatol 8: 579-594
MeSH Terms: Acinar Cells, Animals, Carcinogenesis, Carcinoma, Pancreatic Ductal, Cell Transformation, Neoplastic, Disease Models, Animal, Genes, ras, Metaplasia, Mice, Mutation, Pancreatic Neoplasms, Pancreatitis, Chronic, Precancerous Conditions, Proto-Oncogene Proteins p21(ras), Signal Transduction
Show Abstract · Added August 6, 2019
BACKGROUND & AIMS - Activating mutation of the KRAS gene is common in some cancers, such as pancreatic cancer, but rare in other cancers. Chronic pancreatitis is a predisposing condition for pancreatic ductal adenocarcinoma (PDAC), but how it synergizes with KRAS mutation is not known.
METHODS - We used a mouse model to express an activating mutation of Kras in conjunction with obstruction of the main pancreatic duct to recapitulate a common etiology of human chronic pancreatitis. Because the cell of origin of PDAC is not clear, Kras mutation was introduced into either duct cells or acinar cells.
RESULTS - Although Kras expression in both cell types was protective against damage-associated cell death, chronic pancreatitis induced p53, p21, and growth arrest only in acinar-derived cells. Mutant duct cells did not elevate p53 or p21 expression and exhibited increased proliferation driving the appearance of PDAC over time.
CONCLUSIONS - One mechanism by which tissues may be susceptible or resistant to KRAS-initiated tumorigenesis is whether they undergo a p53-mediated damage response. In summary, we have uncovered a mechanism by which inflammation and intrinsic cellular programming synergize for the development of PDAC.
Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.
2 Communities
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15 MeSH Terms
Location-dependent maintenance of intrinsic susceptibility to mTORC1-driven tumorigenesis.
Rushing GV, Brockman AA, Bollig MK, Leelatian N, Mobley BC, Irish JM, Ess KC, Fu C, Ihrie RA
(2019) Life Sci Alliance 2:
MeSH Terms: Adolescent, Animals, Astrocytoma, Carcinogenesis, Cells, Cultured, Child, Child, Preschool, Disease Susceptibility, Female, Humans, Lateral Ventricles, Male, Mechanistic Target of Rapamycin Complex 1, Mice, Mice, Inbred C57BL, Neural Stem Cells, Signal Transduction, Thyroid Nuclear Factor 1, Tuberous Sclerosis
Show Abstract · Added March 27, 2019
Neural stem/progenitor cells (NSPCs) of the ventricular-subventricular zone (V-SVZ) are candidate cells of origin for many brain tumors. However, whether NSPCs in different locations within the V-SVZ differ in susceptibility to tumorigenic mutations is unknown. Here, single-cell measurements of signal transduction intermediates in the mechanistic target of rapamycin complex 1 (mTORC1) pathway reveal that ventral NSPCs have higher levels of signaling than dorsal NSPCs These features are linked with differences in mTORC1-driven disease severity: introduction of a pathognomonic mutation only results in formation of tumor-like masses from the ventral V-SVZ. We propose a direct link between location-dependent intrinsic growth properties imbued by mTORC1 and predisposition to tumor development.
© 2019 Rushing et al.
2 Communities
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19 MeSH Terms
Chemokines Modulate Immune Surveillance in Tumorigenesis, Metastasis, and Response to Immunotherapy.
Vilgelm AE, Richmond A
(2019) Front Immunol 10: 333
MeSH Terms: Animals, Antineoplastic Agents, Immunological, Biomarkers, Carcinogenesis, Chemokines, Disease Progression, Humans, Immunologic Surveillance, Immunomodulation, Immunotherapy, Molecular Targeted Therapy, Neoplasm Metastasis, Neoplasm Staging, Neoplasms, Prognosis, Receptors, Chemokine, Treatment Outcome
Show Abstract · Added March 26, 2019
Chemokines are small secreted proteins that orchestrate migration and positioning of immune cells within the tissues. Chemokines are essential for the function of the immune system. Accumulating evidence suggest that chemokines play important roles in tumor microenvironment. In this review we discuss an association of chemokine expression and activity within the tumor microenvironment with cancer outcome. We summarize regulation of immune cell recruitment into the tumor by chemokine-chemokine receptor interactions and describe evidence implicating chemokines in promotion of the "inflamed" immune-cell enriched tumor microenvironment. We review both tumor-promoting function of chemokines, such as regulation of tumor metastasis, and beneficial chemokine roles, including stimulation of anti-tumor immunity and response to immunotherapy. Finally, we discuss the therapeutic strategies target tumor-promoting chemokines or induce/deliver beneficial chemokines within the tumor focusing on pre-clinical studies and clinical trials going forward. The goal of this review is to provide insight into comprehensive role of chemokines and their receptors in tumor pathobiology and treatment.
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17 MeSH Terms
Kaiso is required for MTG16-dependent effects on colitis-associated carcinoma.
Short SP, Barrett CW, Stengel KR, Revetta FL, Choksi YA, Coburn LA, Lintel MK, McDonough EM, Washington MK, Wilson KT, Prokhortchouk E, Chen X, Hiebert SW, Reynolds AB, Williams CS
(2019) Oncogene 38: 5091-5106
MeSH Terms: Adenocarcinoma, Animals, Carcinogenesis, Colitis, Colonic Neoplasms, Female, HCT116 Cells, HEK293 Cells, Humans, Inflammation, Intestinal Mucosa, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Repressor Proteins, Transcription Factors
Show Abstract · Added March 16, 2019
The myeloid translocation gene family member MTG16 is a transcriptional corepressor that relies on the DNA-binding ability of other proteins to determine specificity. One such protein is the ZBTB family member Kaiso, and the MTG16:Kaiso interaction is necessary for repression of Kaiso target genes, such as matrix metalloproteinase-7. Using the azoxymethane and dextran sodium sulfate (AOM/DSS) murine model of colitis-associated carcinoma, we previously determined that MTG16 loss accelerates tumorigenesis and inflammation. However, it was unknown whether this effect was modified by Kaiso-dependent transcriptional repression. To test for a genetic interaction between MTG16 and Kaiso in inflammatory carcinogenesis, we subjected single and double knockout (DKO) mice to the AOM/DSS protocol. Mtg16 mice demonstrated increased colitis and tumor burden; in contrast, disease severity in Kaiso mice was equivalent to wild-type controls. Surprisingly, Kaiso deficiency in the context of MTG16 loss reversed injury and pro-tumorigenic responses in the intestinal epithelium following AOM/DSS treatment, and tumor numbers were returned to near to wild-type levels. Transcriptomic analysis of non-tumor colon tissue demonstrated that changes induced by MTG16 loss were widely mitigated by concurrent Kaiso loss, and DKO mice demonstrated downregulation of metabolism and cytokine-associated gene sets with concurrent activation of DNA damage checkpoint pathways as compared with Mtg16. Further, Kaiso knockdown in intestinal enteroids reduced stem- and WNT-associated phenotypes, thus abrogating the induction of these pathways observed in Mtg16 samples. Together, these data suggest that Kaiso modifies MTG16-driven inflammation and tumorigenesis and suggests that Kaiso deregulation contributes to MTG16-dependent colitis and CAC phenotypes.
1 Communities
3 Members
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17 MeSH Terms
α-Difluoromethylornithine reduces gastric carcinogenesis by causing mutations in .
Sierra JC, Suarez G, Piazuelo MB, Luis PB, Baker DR, Romero-Gallo J, Barry DP, Schneider C, Morgan DR, Peek RM, Gobert AP, Wilson KT
(2019) Proc Natl Acad Sci U S A 116: 5077-5085
MeSH Terms: Animals, Bacterial Proteins, Carcinogenesis, DNA Damage, Eflornithine, Gene Deletion, Gene Rearrangement, Gerbillinae, Helicobacter pylori, Male, Mutation, Oxidative Stress, RNA, Messenger, Stomach Neoplasms, Virulence
Show Abstract · Added February 26, 2019
Infection by is the primary cause of gastric adenocarcinoma. The most potent virulence factor is cytotoxin-associated gene A (CagA), which is translocated by a type 4 secretion system (T4SS) into gastric epithelial cells and activates oncogenic signaling pathways. The gene encodes for a key component of the T4SS and can undergo gene rearrangements. We have shown that the cancer chemopreventive agent α-difluoromethylornithine (DFMO), known to inhibit the enzyme ornithine decarboxylase, reduces -mediated gastric cancer incidence in Mongolian gerbils. In the present study, we questioned whether DFMO might directly affect pathogenicity. We show that output strains isolated from gerbils treated with DFMO exhibit reduced ability to translocate CagA in gastric epithelial cells. Further, we frequently detected genomic modifications in the middle repeat region of the gene of output strains from DFMO-treated animals, which were associated with alterations in the CagY protein. Gerbils did not develop carcinoma when infected with a DFMO output strain containing rearranged or the parental strain in which the wild-type was replaced by with DFMO-induced rearrangements. Lastly, we demonstrate that in vitro treatment of by DFMO induces oxidative DNA damage, expression of the DNA repair enzyme MutS2, and mutations in , demonstrating that DFMO directly affects genomic stability. Deletion of abrogated the ability of DFMO to induce rearrangements directly. In conclusion, DFMO-induced oxidative stress in leads to genomic alterations and attenuates virulence.
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15 MeSH Terms
Nod1 Imprints Inflammatory and Carcinogenic Responses toward the Gastric Pathogen .
Suarez G, Romero-Gallo J, Piazuelo MB, Sierra JC, Delgado AG, Washington MK, Shah SC, Wilson KT, Peek RM
(2019) Cancer Res 79: 1600-1611
MeSH Terms: Animals, Carcinogenesis, Cytokines, Gastric Mucosa, Helicobacter pylori, Mice, Mice, Inbred C57BL, Mice, Knockout, Nod1 Signaling Adaptor Protein, Stomach Neoplasms
Show Abstract · Added February 23, 2019
() is the strongest known risk for gastric cancer. The type IV secretion system is an oncogenic locus that translocates peptidoglycan into host cells, where it is recognized by NOD1, an innate immune receptor. Beyond this, the role of NOD1 in -induced cancer remains undefined. To address this knowledge gap, we infected two genetic models of Nod1 deficiency with the strain PMSS1: C57BL/6 mice, which rarely develop cancer, and INS-GAS FVB/N mice, which commonly develop cancer. Infected C57BL/6 and INS-GAS mice acutely developed more severe gastritis, and INS-GAS mice developed gastric dysplasia more frequently compared with mice. Because genotype status did not alter microbial phenotypes of adapted , we investigated host immunologic responses. infection of mice led to significantly increased gastric mucosal levels of Th1, Th17, and Th2 cytokines compared with Nod1 wild-type (WT) mice. To define the role of specific innate immune cells, we quantified cytokine secretion from -infected primary gastric organoids generated from WT or mice that were cocultured with or without WT or macrophages. Infection increased cytokine production from gastric epithelial cells and macrophages and elevations were significantly increased with Nod1 deficiency. Furthermore, infection altered the polarization status of macrophages compared with macrophages. Collectively, these studies demonstrate that loss of Nod1 augments inflammatory and injury responses to . Nod1 may exert its restrictive role by altering macrophage polarization, leading to immune evasion and microbial persistence. SIGNIFICANCE: These findings suggest that manipulation of NOD1 may represent a novel strategy to prevent or treat pathologic outcomes induced by infection.
©2019 American Association for Cancer Research.
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10 MeSH Terms